Biology subjects

Zhao, W.

Publications and source records attributed to Zhao, W..

At least 289 records · Page 16Linked to original sources

bioRxiv2021

Genome Warehouse: A Public Repository Housing Genome-scale Data

The Genome Warehouse (GWH) is a public repository housing genome assembly data for a wide range of species and delivering a series of web services for genome data submission, storage, release, and sharing. As one of the core resources in the National Genomics Data Center (NGDC), part of the China National Center for Bioinformation (CNCB, https://bigd.big.ac.cn/), GWH accepts both full genome and partial genome (chloroplast, mitochondrion, and plasmid) sequences with different assembly levels, as well as an update of existing genome assemblies. For each assembly, GWH collects detailed genome-related metadata including biological project and sample, and genome assembly information, in addition to genome sequence and annotation. To archive high-quality genome sequences and annotations, GWH is equipped with a uniform and standardized procedure for quality control. Besides basic browse and search functionalities, all released genome sequences and annotations can be visualized with JBrowse. By December 2020, GWH has received 17,264 direct submissions covering a diversity of 949 species, and has released 3370 of them. Collectively, GWH serves as an important resource for genome-scale data management and provides free and publicly accessible data to support research activities throughout the world. GWH is publicly accessible at https://bigd.big.ac.cn/gwh/.

bioinformatics↗

bioRxiv2021

Genomic analyses of 10,376 individuals provides comprehensive map of genetic variations, structure and reference haplotypes for Chinese population

Here, we initiated the Westlake BioBank for Chinese (WBBC) pilot project with 4,535 whole-genome sequencing individuals and 5,481 high-density genotyping individuals. We identified 80.99 million SNPs and INDELs, of which 38.6% are novel. The genetic evidence of Chinese population structure supported the corresponding geographical boundaries of the Qinling-Huaihe Line and Nanling Mountains. The genetic architecture within North Han was more homogeneous than South Han, and the history of effective population size of Lingnan began to deviate from the other three regions from 6 thousand years ago. In addition, we identified a novel locus (SNX29) under selection pressure and confirmed several loci associated with alcohol metabolism and histocompatibility systems. We observed significant selection of genes on epidermal cell differentiation and skin development only in southern Chinese. Finally, we provided an online imputation server (https://wbbc.westlake.edu.cn/) which could result in higher imputation accuracy compared to the existing panels, especially for lower frequency variants.

genetics↗

bioRxiv2021

Modeling of histone modifications reveals formation mechanism and function of bivalent chromatin

Bivalent chromatin is characterized by occupation of both activating histone modifications and repressive histone modifications. While bivalent chromatin is known to link with many biological processes, the mechanisms responsible for its multiple functions remain unclear. Here, we develop a mathematical model that involves antagonistic histone modifications H3K4me3 and H3K27me3 to capture the key features of bivalent chromatin. Three necessary conditions for the emergence of bivalent chromatin are identified, including advantageous methylating activity over demethylating activity, frequent noise conversions of modifications, and sufficient nonlinearity. The first condition is further confirmed by analyzing the experimental data from a recent study. Investigation of the composition of bivalent chromatin reveals that bivalent nucleosomes carrying both H3K4me3 and H3K27me3 account for no more than half of nucleosomes at the bivalent chromatin domain. We identify that bivalent chromatin not only allows transitions to multiple states but also serves as a stepping stone to facilitate a step-wise transition between repressive chromatin state and activating chromatin state, and thus elucidate crucial roles of bivalent chromatin in mediating phenotypical plasticity during cell fate determination.

systems biology↗

bioRxiv2021

Discovering hidden brain network responses to naturalistic stimuli via tensor component analysis of multi-subject fMRI data

The study of brain network interactions during naturalistic stimuli facilitates a deeper understanding of human brain function. Intersubject correlation (ISC) analysis of functional magnetic resonance imaging (fMRI) data is a widely used method that can measure neural responses to naturalistic stimuli that are consistent across subjects. However, interdependent correlation values in ISC artificially inflated the degrees of freedom, which hinders the investigation of individual differences. Besides, the existing ISC model mainly focus on similarities between subjects but fails to distinguish neural responses to different stimuli features. To estimate large-scale brain networks evoked with naturalistic stimuli, we propose a novel analytic framework to characterize shared spatio-temporal patterns across subjects in a purely data-driven manner. In the framework, a third-order tensor is constructed from the timeseries extracted from all brain regions from a given parcellation, for all participants, with modes of the tensor corresponding to spatial distribution, time series and participants. Tensor component analysis (TCA) will then reveal spatially and temporally shared components, i.e., naturalistic stimuli evoked networks, their temporal courses of activity and subject loadings of each component. To enhance the reproducibility of the estimation with TCA, a novel spectral clustering method, tensor spectral clustering, was proposed and applied to evaluate the stability of TCA algorithm. We demonstrate the effectiveness of the proposed framework via simulations and real fMRI data collected during a motor task with a traditional fMRI study design. We also apply the proposed framework to fMRI data collected during passive movie watching to illustrate how reproducible brain networks are identified evoked by naturalistic movie viewing.

neuroscience↗

bioRxiv2020

Secondary rewards acquire enhanced incentive motivation via increasing anticipatory activity of the lateral orbitofrontal cortex

The motivation to strive for and consume primary rewards such as palatable food is bound by internal satiation and devaluation mechanisms, yet secondary rewards such as money may not be bound by these regulatory mechanisms. The present study therefore aimed at determining diverging devaluation trajectories for primary (chocolate milk) and secondary (money) reinforcers on the behavioral and neural level. Satiation procedures combined with a choice (Experiment 1) and an incentive delay (Experiment 2) paradigm consistently revealed decreased hedonic value for the primary reward as reflected by decreasing hedonic evaluation and choice preference, while hedonic value and preferences for the secondary reward increased. Concomitantly acquired functional near-infrared spectroscopy (fNIRS) data during the incentive delay paradigm revealed that increasing value of the secondary reward was accompanied by increasing anticipatory activation in the lateral orbitofrontal cortex, while during the consummatory phase the secondary reinforcer associated with higher medial orbitofrontal activity irrespective of devaluation stage. Overall, the findings suggest that - in contrast to primary reinforcers - secondary reinforcers can acquire progressively enhanced incentive motivation with repeated receipt, suggesting a mechanism which could promote escalating striving to obtain secondary rewards.

neuroscience↗

bioRxiv2020

RAD51AP1 mediates RAD51 activity through nucleosome interaction

RAD51 Associated Protein 1 (RAD51AP1) is a key protein in the homologous recombination DNA repair pathway (HR). Loss of RAD51AP1 leads to defective HR, genome instability and telomere erosion. RAD51AP1 physically interacts with the RAD51 recombinase and promotes RAD51-mediated capture of the donor DNA, synaptic complex assembly and displacement-loop formation when tested with synthetic, nucleosome-free DNA substrates in vitro. In cells, however, DNA is packaged into chromatin, posing an additional barrier to the complexities of the HR reaction. How RAD51AP1 functions as an HR activator in the context of chromatin has remained unclear. In this study, we show that RAD51AP1 binds to Nucleosome Core Particles (NCPs). We identified a C-terminal region in RAD51AP1 and its previously mapped DNA binding domain as critical for mediating the association between RAD51AP1 and both the NCP and the histone octamer. We show that RAD51AP1 is capable of promoting duplex DNA capture and initiating joint-molecule formation with the NCP and chromatinized template DNA, respectively. Together, our results suggest that RAD51AP1 directly assists the RAD51-mediated search of donor DNA in chromatin. We present a model, in which RAD51AP1 anchors the DNA template through affinity for its nucleosomes to the RAD51-ssDNA nucleoprotein filament.

biochemistry↗

bioRxiv2020

Drosophila larval light avoidance is negatively regulated by temperature through two pairs of central brain neurons

Animals innate avoidance behavior is crucial for its survival. It subjects to modulation by environmental conditions in addition to the commanding sensorimotor transformation pathway. Although much has been known about the commanding neural basis, relatively less is known about how innate avoidance behavior is shaped by external conditions. Here in this paper, we report that Drosophila larvae showed stronger light avoidance at lower temperatures than at higher temperatures. Such negative regulation of light avoidance by temperature was abolished by blocking two pairs of central brain neurons, ACLPR60F09 neurons, that were responsive to both light and temperature change, including cooling and warming. ACLPR60F09 neurons could be excited by pdf-LaN neurons in the visual pathway. On the downstream side, they could inhibit the CLPNR82B09 neurons that command light induced reorientation behavior. Compared with at warm temperature, ACLPR60F09 neurons response to light was decreased at cool temperature so that the inhibition on CLPNR82B09 neurons was relieved and the light induced avoidance was enhanced. Our result proposed a neural mechanism underlying cross-modal modulation of animal innate avoidance behavior.

neuroscience↗

bioRxiv2020

Beyond fear centers: a distributed fMRI-based neuromarker for the subjective experience of fear

The specific neural systems underlying the subjective feeling of fear remain vigorously debated in affective neuroscience. Here, we combined functional MRI with machine learning to identify and evaluate a sensitive and generalizable neural signature predictive of the momentary self-reported subjective fear experience across discovery (n=67), validation (n=20) and generalization (n=31) cohorts. We systematically demonstrate that accurate fear prediction crucially requires distributed brain systems, with important contributions from cortical (e.g., prefrontal, midcingulate and insular cortices) and subcortical (e.g., thalamus, periaqueductal gray, basal forebrain and amygdala) regions. We further demonstrate that the neural representation of subjective fear is distinguishable from the representation of conditioned threat and general negative affect. Overall, our findings suggest that subjective fear, which exhibits distinct neural representation with some other aversive states, is encoded in distributed systems rather than isolated fear centers. This signature provides a neuromarker for monitoring fear-related neuropathology and evaluating novel treatments targeting pathological fear.

neuroscience↗

bioRxiv2020

Reprogrammed CRISPR-Cas13b suppresses SARS-CoV-2 replication and circumvents its mutational escape through mismatch tolerance

Mutation-driven evolution of SARS coronavirus-2 (SARS-CoV-2) highlights the need for innovative approaches that simultaneously suppress viral replication and circumvent viral escape routes from host immunity and antiviral therapeutics. Here, we employed genome-wide computational prediction and singlenucleotide resolution screening to reprogram CRISPR-Cas13b against SARS-CoV-2 genomic and subgenomic RNAs. Reprogrammed Cas13b effectors targeting accessible regions of Spike and Nucleocapsid transcripts achieved >98% silencing efficiency in virus free-models. Further, optimized and multiplexed gRNAs suppressed viral replication by up to 90% in mammalian cells infected with replication-competent SARS-CoV-2. Unexpectedly, the comprehensive mutagenesis of guide-target interaction demonstrated that single-nucleotide mismatches do not impair the capacity of a potent single gRNA to simultaneously suppress ancestral and mutated SARS-CoV-2 in infected mammalian cells, including the highly infectious and globally disseminated Spike D614G mutant. The specificity, efficiency and rapid deployment properties of reprogrammed Cas13b described here provide a molecular blueprint of antiviral therapeutics to simultaneously suppress a wide range of SARS-CoV-2 mutants, and is readily adaptable to other emerging pathogenic viruses.

microbiology↗

bioRxiv2020

The human ApoE4 variant reduces functional recovery and neuronal sprouting after incomplete spinal cord injury in male mice

Spinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two ApoE4 alleles show worse functional outcomes and longer hospital stays after SCI but the cellular and molecular underpinnings for this genetic link remain poorly understood. Thus, there is a great need to generate animal models to accurately replicate the genetic determinants of outcomes after SCI to spur development of treatments that improve physical function. Here, we examined outcomes after a moderate contusion SCI of transgenic mice expressing human ApoE3 or ApoE4. ApoE4 mice have worse locomotor function and coordination after SCI. Histological examination revealed greater glial staining in ApoE4 mice after SCI associated with reduced levels of neuronal sprouting markers. Bulk RNA sequencing revealed that subcellular processes (SCPs), such as extracellular matrix organization and inflammatory responses, were highly-ranked among upregulated genes at 7 days after SCI in ApoE4 variants. Conversely, SCPs related to neuronal action potential and neuron projection development were increased in ApoE3 mice at 21 days. In summary, our results reveal a clinically relevant SCI mouse model that recapitulates the influence of ApoE genotypes on post-SCI function in individuals who carry these alleles and suggest that the mechanisms underlying worse recovery for ApoE4 animals involve glial activation and loss of sprouting and synaptic activity.

neuroscience↗

bioRxiv2020

Duple extinguishment of COVID-19: single compound synergized inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokines in vitro/vivo

We firstly disclose single compound yields better therapeutic outcome than Remdesivir in COVID-19 hamster treatments as it is armed with direct inhibition viral replication and intrinsic suppression inflammatory cytokines expression. Crystal data reveals that Au (I), released from Au22Glutathione18 (GA), covalently binds thiolate of Cys145 of SARS-CoV-2 Mpro. GA directly decreases SARS-CoV-2 viral replication (EC50: ~0.24 M) and intrinsically down-regulates NF{kappa}B pathway therefore significantly inhibiting expression of inflammatory cytokines in cells. The lung viral load and inflammatory cytokines in GA-treated COVID-19 transgenic mice are found to be significantly lower than that of control mice. When COVID-19 golden hamsters are treated by GA, the lung inflammatory cytokines levels are significantly lower than that of Remdesivir while their lung viral load are decreased to same level. The pathological results show that GA treatment significantly reduce lung inflammatory injuries when compared to that of Remdesivir-treated COVID-19 golden hamsters. One Sentence SummaryWe found that gold cluster molecule directly inhibits SARS-CoV-2 replication and intrinsically suppresses inflammatory cytokines expression in COVID-19 transgenic mouse and golden hamster model, gold cluster providing a better lung injury protection than Remdesivir in COVID-19 golden hamsters via intranasally dropping administration.

microbiology↗

bioRxiv2020

A parental transcriptional response to microsporidia infection induces inherited immunity in offspring

Inherited immunity is an emerging field and describes how the transfer of immunity from parents to offspring can promote progeny survival in the face of infection. The mechanisms of how inherited immunity is induced are mostly unknown. The intracellular parasite Nematocida parisii is a natural microsporidian pathogen of Caenorhabditis elegans. Here, we show that N. parisii-infected worms produce primed offspring that are resistant to microsporidia infection. We find that immunity is induced in a dose dependent manner and lasts for a single generation. Intergenerational immunity prevents host cell invasion by N. parisii and also enhances survival to the bacterial pathogen Pseudomonas aeruginosa. Further, we show that inherited immunity is triggered by the host transcriptional response to infection, which can also be induced through maternal somatic depletion of negative regulators PALS-22 and the retinoblastoma protein ortholog LIN-35. We show that other biotic and abiotic stresses, such as viral infection and cadmium exposure, that induce a similar transcriptional response to microsporidia can also induce immunity in progeny. Our results demonstrate that distinct stimuli can induce inherited immunity to provide resistance against multiple classes of pathogens. These results show that activation of an innate immune response can provide protection against pathogens not only within a generation, but also in the next generation.

microbiology↗

bioRxiv2020

Blocking of EGFR Signaling is a Latent Strategy for the Improvement of Prognosis of HPV Induced Cancer

Human papillomavirus (HPV) is a dsDNA virus and its high-risk subtypes increase cancer risks. Yet, the mechanism of HPV infection and pathogenesis still remain unclear. Therefore, understanding the molecular mechanisms, and the pathogenesis of HPV are crucial in the prevention of HPV related cancers. In this study, we analyzed cervix squamous cell carcinoma (CESC) and head and neck carcinoma (HNSC) combined data to investigate various HPV induced cancer common feature. We showed that epidermal growth factor receptor (EGFR) was downregulated in HPV positive (HPV+) cancer, and that HPV+ cancer patients exhibited better prognosis than HPV negative (HPV-) cancer patients. Our study also showed that TP53 mutation rate is lower in HPV+ cancer than in HPV- cancer and that TP53 can be modulated by HPV E7 protein. However, there was no significant difference in the expression of wildtype TP53 in both groups. Subsequently, we constructed HPV-human interaction network and found that EGFR is a critical factor. From the network, we also noticed that EGFR is regulated by HPV E7 protein and hsa-miR-944. Moreover, while phosphorylated EGFR is associated with a worse prognosis, EGFR total express level is not significantly correlated with prognosis. This indicates that EGFR activation will induce a worse outcome in HPV+ cancer patients. Further enrichment analysis showed that EGFR downstream pathway and cancer relative pathway are diversely activated in HPV+ cancer and HPV- cancer. In summary, HPV E7 protein downregulates EGFR that downregulates phosphorylated EGFR and inhibit EGFR related pathways which in turn and consequently induce better prognosis. ImportanceAlthough HPV infection has been studied in various cancer types, there are only limited studies that have focused on the common effect of HPV related cancer. Consequently, this study focused on CESC and HNSC, two cancer types with high HPV infection proportion in cohort, thereby, intending to dig out the common effects and mechanisms of HPV+ cancers. Unlike some virus-human interaction prediction studies, the P-HIPSter database provides virus-human protein interaction based on protein structure prediction. Through this data, our interaction network was able to uncover previously unnoticed protein interactions. Our finding revealed that HPV infection caused various gene expression differences, and a great amount of which interact with EGFR, a cancer related gene. Therefore, since EGFR is associated with HPV+ cancer patients survival, some FDA proved EGFR inhibitors would be potential anti-HPV drugs.

microbiology↗

bioRxiv2020

SMARCAD1 Mediated Active Replication Fork Stability Maintains Genome Integrity

Stalled fork protection pathway mediated by BRCA1/2 proteins is critical for replication fork stability that has implications in tumorigenesis. However, it is unclear if additional mechanisms are required to maintain replication fork stability. We describe a novel mechanism by which the chromatin remodeler SMARCAD1 stabilizes active replication forks that is essential for resistance towards replication poisons. We find that loss of SMARCAD1 results in toxic enrichment of 53BP1 at replication forks which mediates untimely dissociation of PCNA via the PCNA-unloader, ATAD5. Faster dissociation of PCNA causes frequent fork stalling, inefficient fork restart and accumulation of single-stranded DNA resulting in genome instability. Although, loss of 53BP1 in SMARCAD1 mutants restore PCNA levels, fork restart efficiency, genome stability and tolerance to replication poisons; this requires BRCA1 mediated fork protection. Interestingly, fork protection challenged BRCA1-deficient naive- or PARPi-resistant tumors require SMARCAD1 mediated active fork stabilization to maintain unperturbed fork progression and cellular proliferation.

cell biology↗

bioRxiv2020

A Bioelectric Neural Interface Towards Intuitive Prosthetic Control For Amputees

ObjectiveWhile prosthetic hands with independently actuated digits have become commercially available, state-of-the-art human-machine interfaces (HMI) only permit control over a limited set of grasp patterns, which does not enable amputees to experience sufficient improvement in their daily activities to make an active prosthesis useful. ApproachHere we present a technology platform combining fully-integrated bioelectronics, implantable intrafascicular microelectrodes and deep learning-based artificial intelligence (AI) to facilitate this missing bridge by tapping into the intricate motor control signals of peripheral nerves. The bioelectric neural interface includes an ultra-low-noise neural recording system to sense electroneurography (ENG) signals from microelectrode arrays implanted in the residual nerves, and AI models employing the recurrent neural network (RNN) architecture to decode the subjects motor intention. Main resultsA pilot human study has been carried out on a transradial amputee. We demonstrate that the information channel established by the proposed neural interface is sufficient to provide high accuracy control of a prosthetic hand up to 15 degrees of freedom (DOF). The interface is intuitive as it directly maps complex prosthesis movements to the patients true intention. SignificanceOur study layouts the foundation towards not only a robust and dexterous control strategy for modern neuroprostheses at a near-natural level approaching that of the able hand, but also an intuitive conduit for connecting human minds and machines through the peripheral neural pathways. Clinical trialDExterous Hand Control Through Fascicular Targeting (DEFT). Identifier: NCT02994160.

bioengineering↗

bioRxiv2020

The global landscape of SARS-CoV-2 genomes, variants, and haplotypes in 2019nCoVR

On 22 January 2020, the National Genomics Data Center (NGDC), part of the China National Center for Bioinformation (CNCB), created the 2019 Novel Coronavirus Resource (2019nCoVR), an open-access SARS-CoV-2 information resource. 2019nCoVR features a comprehensive integration of sequence and clinical information for all publicly available SARS-CoV-2 isolates, which are manually curated with value-added annotations and quality evaluated by our in-house automated pipeline. Of particular note, 2019nCoVR performs systematic analyses to generate a dynamic landscape of SARS-CoV-2 genomic variations at a global scale. It provides all identified variants and detailed statistics for each virus isolate, and congregates the quality score, functional annotation, and population frequency for each variant. It also generates visualization of the spatiotemporal change for each variant and yields historical viral haplotype network maps for the course of the outbreak from all complete and high-quality genomes. Moreover, 2019nCoVR provides a full collection of SARS-CoV-2 relevant literature on COVID-19 (Coronavirus Disease 2019), including published papers from PubMed as well as preprints from services such as bioRxiv and medRxiv through Europe PMC. Furthermore, by linking with relevant databases in CNCB-NGDC, 2019nCoVR offers data submission services for raw sequence reads and assembled genomes, and data sharing with National Center for Biotechnology Information. Collectively, all SARS-CoV-2 genome sequences, variants, haplotypes and literature are updated daily to provide timely information, making 2019nCoVR a valuable resource for the global research community. 2019nCoVR is accessible at https://bigd.big.ac.cn/ncov/.

genomics↗

bioRxiv2020

Medial prefrontal activity at encoding determines recognition of threatening faces after 1.5 years

Studies demonstrated that faces with threatening emotional expressions are better remembered than non-threatening faces. However, whether this memory advantage persists over years and which neural systems underlie such an effect remains unknown. Here, we investigated recognition of incidentally encoded faces with angry, fearful, happy, sad and neutral expressions over >1.5 years (N= 89). Univariate analyses showed that threatening faces (angry, fearful) were better recognized than happy and neutral faces after >1.5 years, and that the threat-related memory enhancement was driven by forgetting of non-threatening faces. Multivariate principal component analysis (PCA) confirmed the discriminative performance between threatening and non-threatening faces. With an innovative Behavioral Pattern Similarity Analysis (BPSA) approach and functional magnetic resonance imaging (fMRI) acquisition during encoding, we further found that the long-term memory advantage for threatening faces were underpinned by differential neural encoding in the left inferior occipital gyrus (IOG) and right ventromedial prefrontal/orbitofrontal cortex (vmPFC/OFC). Our study provides the first evidence that threatening facial expressions lead to persistent face recognition over periods of >1.5 years and differential encoding-related activity in the visual cortex and medial prefrontal cortex may underlie this effect.

neuroscience↗

bioRxiv2020

Scaffold-scaffold interactions regulate cell polarity in a bacterium

The localization of two biochemically distinct signaling hubs at opposite cell poles provides the foundation for asymmetric cell division in Caulobacter crescentus. Here we identify an interaction between the scaffolds PodJ and PopZ that regulates the assembly of the new cell pole signaling complex. Time-course imaging of a mCherry-sfGFP-PopZ fluorescent timer throughout the cell cycle revealed that existing PopZ resides at the old cell pole while newly translated PopZ accumulates at the new cell pole. Our studies suggest that interactions between PodJ and PopZ promotes the sequestration of older PopZ and robust accumulation of newl PopZ at the new cell pole. Elimination of the PodJ-PopZ interaction impacts PopZ client proteins, leading to chromosome segregation defects in one-third of cells. Additionally, this PopZ-PodJ interaction is crucial for anchoring PodJ and preventing PodJ extracellular loss at the old cell pole through unknown mechanism. Therefore, segregation of PopZ protein at the old pole and recruitment of newly translated PopZ at the new pole via the PodJ scaffold ensures stringent inheritance and maintenance of the polarity axis within dividing C. crescentus cells.

microbiology↗